The chronic administration of amphetamine (AMPH) to humans results in tolerance to the mood elevation produced by the drug, but can result in sensitization to its psychotic properties. Similarly, the chronic administration of AMPH to rats produces qualitatively distinct behavioral changes depending on the behavior which is monitored. Some components of the behavioral response exhibit tolerance, whereas other components exhibit augmentation (reverse tolerance). The latter can be further dissociated into at least three distinct components. Although dopamine (DA) appears to play a crucial role in all of the acute behavioral effects of AMPH, a dopaminergic biochemical correlate to the chronic effects of AMPH has not been identified. These observations, coupled with apparent discrepancies in the literature between the presumed mechanisms of action of AMPH and the biochemical and electrophysiological consequences of the drug, suggest that the role of DA in AMPH-induced behavioral changes requires reevaluation. Because of the dynamic nature of neurotransmission, such a reevaluation should be performed in the awake, freely-moving animal, and should consider those parameters most relevant to DA neurotransmission, i.e., the amount of transmitter reaching the synaptic cleft, and the functional consequences of transmitter-receptor interactions for post-synaptic function. Finally, a reevaluation should consider alternative neurochemical substrates for AMPH's action, which our recent data suggest may be serotonin (5HT). The proposed research is directed at first, reevaluating consequences of AMPH for striatal dopaminergic and serotonergic presynaptic and postsynaptic function, and second, defining the role(s) of the AMPH-DA and AMPH-5HT interactions in the behavioral consequences of acute and chronic AMPH administration. These objectives will be achieved by: (1) directly evaluating extracellular DA levels in response to AMPH, through push-pull perfusion of the striatum, as the most appropriate approach to gain new insights into the mechanism of interaction of AMPH with dopaminergic systems; (2) coevaluating 5HT levels in perfusate to allow a delineation of the degree to which AMPH can interact with neurotransmitter; (3) evaluating the striatal cholinergic response to AMPH as a direct physiological measure of the postsynaptic consequences of changes in DA and 5HT function; and (4) quantitating the behavioral response in the same animals to establish the most accurate biochemical-behavioral correlates of AMPH administration.